Monoclonal antibodies (mAbs) have been developed into a highly effective class of therapeutic molecules, with global growth of 37% between 2001 and 2002. Since their discovery in 1975, mAbs have been described as magic bullets with the potential to seek out and target specific molecules and bind them with high affinity. Early treatment efforts using rodent systems to develop mAbs for use in humans proved ineffective due to the strong immune responses they elicit in humans, limiting their half life in the body and potentially causing anaphylaxis. Strategies to overcome this obstacle have included humanization of rodent-derived mAbs and development of fully hu-mAbs. There are 24 mAb therapeutics on the market, and mAbs account for more than 25% of the current drugs in the FDA pipeline and ~50% of all new drug launches. Current technologies for hu- mAb development are sub-optimal in that the therapeutics derived from these approaches are either 1) not fully human resulting in increased toxicity, or 2) require several rounds of maturation due to achieve high affinity resulting in longer, more costly development. The goal of this Phase I proposal is to adapt our patented murine reactivation platform to human B cells immunized in the context of the SCID-huPBL mouse, ultimately leading to a new method (human reactivation) for the development of fully-human mAbs. Reactivation is the technology for selecting, enriching, and amplifying human high affinity antibody producing cells preferentially. Successful completion of this proposal will result in the rapid, efficient, and cos effective development of fully-human high affinitity mAbs, increasing the accessibility of these reagents to drug discovery researchers investigating cancer and other deadly diseases. PUBLIC HEALTH RELEVANCE: Therapeutic monoclonal antibodies are emerging as one of the most effective targeted drug approaches for disease treatment. NeoClone is proposing to adapt its successful monoclonal antibody reactivation technology to enable development of fully-human therapeutic monoclonal antibodies. Successful completion of this grant will demonstrate the feasibility of developing high affinity fully-human therapeutic monoclonal antibodies at low cost, that can be broadly used to treat a variety of diseases, ranging from cancer to infectious disease. The availability of such a powerful therapeutic development platform will provide immense economic benefit by reducing costs associated with drug development, and ultimately lowering healthcare costs while improving the patients' outcome.